Small intestine and kidney tubules play essential roles in the absorption and homeostatic balance of salt and carbohydrates. The major apical membrane transporters that absorb sodium and chloride include the chloride/base exchangers DRA (SLC26A3) and PAT1 (SLC26A6) and the Na+/H+ exchanger NHE3 in the intestine and PAT1 and NHE3 in the kidney proximal tubule. Recent studies from our laboratories demonstrate novel interactions between carbohydrates (glucose and fructose) and DRA, PAT1, and NHE3 in the intestine and kidney tubules. We provide evidence that Glut5 is the major fructose-absorbing transporter in the small intestine (and possibly kidney). Luminal fructose stimulated salt absorption through genomic and nongenomic mechanisms. Luminal fructose activated Slc26a6 (PAT1), resulting in enhanced salt absorption in the small intestine, a response that was significantly diminished in Slc26a6-/- mice and abrogated in Glut5-/- mice. Increased dietary fructose intake enhanced the expression of PAT1, NHE3, and Glut5 in the small intestine. Further, increased dietary fructose intake enhanced salt absorption in the kidney and resulted in hypertension in Slc26a6+/+ mice, a response that was almost abolished in Slc26a6-/- mice (Kidney Int., Aug 08). Glut5-/- mice failed to absorb dietary fructose and became hypotensive;whereas, Glut5+/+ mice thrived and became hypertensive on high fructose intake. The stimulatory effect of fructose on salt absorption in the small intestine was also significantly diminished in DRA ko mice and abolished in NHE3 ko mice. PAT1 is stimulated by the luminal glucose in the small intestine, with subsequent enhancement of salt absorption (Pflugers Arch., Jan. 08). Luminal glucose also activates the apical chloride/base exchanger in the proximal tubule. The stimulatory effect of glucose on PAT1 and NHE3 allows these exchangers to mediate enhanced salt absorption in the intestine after a meal high in glucose or in the kidney proximal tubule in the early stages of diabetes. Coupled with the significant upregulation of PAT1 expression at eight days after the induction of diabetes mellitus (Preliminary Studies), these results strongly suggest that PAT1 and NHE3 may play an important role in enhanced salt absorption in the kidney tubules in the early stages of diabetes mellitus. The purpose of this application is to ascertain the role of major salt and carbohydrate transporters in the small intestine and kidney tubules in the absorption and systemic homeostasis of salt, glucose, and fructose in normal state and in the pathophysiology of fructose-induced hypertension and diabetes-induced hypertension and nephropathy. In vivo and in vitro studies in mice with systemic deletion of Slc26a3 (DRA), Slc26a4 (pendrin), Slc26a6 (PAT1), and Slc26a9 or targeted deletion of NHE3 or Glut5 (Slc2a5) will be utilized for these studies. Understanding the role and regulation of salt and fructose absorbing transporters in the intestine and kidney tubules will provide novel diagnostic and therapeutic insights into morbid disorders includinghypertension, diabetes, and obesity.